Phosphodiesterases (PDEs) are a family of enzymes encoded by 21 genes and subdivided into 11 distinct families according to structural and functional properties. These enzymes metabolically inactivate widely occurring intracellular second messengers, 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP). These two messengers regulate a wide variety of biological processes, including pro-inflammatory mediator production and action, ion channel function, muscle contraction, learning, differentiation, apoptosis, lipogenesis, glycogenolysis, and gluconeogenesis. They do this by activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate a wide variety of substrates including transcription factors and ion channels that regulate innumerable physiological responses. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival. Intracellular concentrations of cAMP and cGMP are strictly regulated by the rate of biosynthesis by cyclases and by the rate of degradation by PDEs. PDEs are hydrolases that inactivate cAMP and cGMP by catalytic hydrolysis of the 3′-ester bond, forming the inactive 5′-monophosphate (Scheme A).

On the basis of substrate specificity, the PDE families can be divided into three groups: i) the cAMP-specific PDEs, which include PDE4, 7 and 8; ii) the cGMP-selective enzymes PDE5, 6, and 9; and iii) the dual-substrate PDEs, PDE1, 2 and 3, as well as PDE10 and 11.
Furthermore, PDEs are expressed differentially throughout the organism, including the central nervous system. Different PDE isozymes therefore may play different physiological functions. Compounds that inhibit selectively PDE families or isozymes may display particular therapeutic activity, fewer side effects, or both.
The discovery of phosphodiesterase 10A (PDE10A) was reported in 1999. Of all the 11 known PDE families, PDE10 has the most restricted distribution with high expression only in the brain and testes.
In the brain, PDE10A mRNA and protein are highly expressed in a majority of striatal Medium Spiny Neurons (MSNs). This unique distribution of PDE10A in the brain, together with its increased pharmacological characterization, indicates a potential use of PDE10A inhibitors for treating neurological and psychiatric disorders like schizophrenia.
In the basal ganglia, MSNs constitute the major site for reception and integration of cortical glutamatergic and midbrain dopaminergic input, and form key output pathways that help discriminate and act on relevant and irrelevant cognitive and motor patterns.
MSNs are GABAergic projection neurons evenly distributed between two distinct pathways. Striatonigral MSNs (in the direct pathway) express the D1 dopamine receptor and neuropeptides dynorphin and substance P; striatopallidal MSNs (in the indirect pathway) express the D2 dopamine receptors and neuropeptide enkephalin. D1 dopamine receptors are positively coupled to cAMP production, while D2 dopamine receptors are negatively coupled to cAMP production. These pathways affect the concentration of extracellular dopamine and modulate motor and behavioural responses.
PDE10 Inhibitors and Schizophrenia
Due to the predominant localisation of PDE10 in MSNs, the majority of research on PDE10 inhibitors has been focused on preclinical models of psychosis.
On the basis of studies performed on knockout mice, the effects of PDE10 inhibition on striatal gene expression have been compared to the effects induced by a D1 agonist and a D2 antagonist.
Schizophrenia is a severe and chronic mental illness that affects approximately 1% of the population. Clinical symptoms are apparent relatively early in life, generally emerging during adolescence or early adulthood. The symptoms of schizophrenia are usually divided into those described as positive, including hallucinations, delusions and disorganised thoughts and those referred to as negative, which include social withdrawal, diminished affection, poverty of speech and the inability to experience pleasure. In addition, schizophrenic patients suffer from cognitive deficits, such as impaired attention and memory. The aetiology of the disease is still unknown, but aberrant neurotransmitter actions have been hypothesized to underlie the symptoms of schizophrenia. The dopaminergic hypothesis is one most often considered, which proposes that hyperactivity of dopamine transmission is responsible for the positive symptoms observed in schizophrenic patients.
The efficacy of currently marketed antipsychotics correlates with their ability to block D2 dopamine receptors. Acute and chronic administration of antipsychotics such as haloperidol has characteristic effects on striatal gene expression. Inhibition of PDE10A has also been observed to produce alterations in striatal gene expression similar to those exerted by haloperidol.
Atypical antipsychotics, such as clozapine, olanzapine, risperidone and paliperidone display a more beneficial profile of extrapyramidal side effects (EPS) and tardive dyskinesia associated with acute and long-term D2 receptor blockade. However there is still a need to develop novel antipsychotics with an extended therapeutic profile and less side effects, e.g. by using approaches beyond dopamine D2 receptor blockade.
PDE10 inhibitors may possess a pharmacological profile similar to that of the atypical antipsychotics, but lacking the non-target related side effects that are often observed with the currently available antipsychotics. Although EPS-like side effects are observed at relatively low doses, they are relatively mild.
Since PDE10 inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10 enzyme, for example neurons that comprise the basal ganglia, PDE10 inhibitors may be useful in treating schizophrenia and additionally, a variety of conditions as described herein such as Parkinson's disease, Huntington's disease, addiction, and depression. PDE10 inhibitors may be also useful in other conditions such as obesity, non-insulin dependent diabetes, bipolar disorder, obsessive compulsive disorder and pain.
The efficacy of PDE10A inhibition in models of cognition and against negative symptoms of schizophrenia has also been suggested by recent in vivo studies in which this mechanism has been associated with increased sociality in the Social Approach/Social Avoidance assay, reversed effect of chronic MK-801 treatment in a forced swim test, enhancement of social odor recognition in mice and improved novel object recognition in rats.